title: Fibroblast growth factor homologous factors modulate cardiac calcium channels.
abstract: BACKGROUND
  Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-14) are intracellular modulators of voltage-gated Na+ channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions.
  
  
  OBJECTIVE
  We aimed to uncover novel roles for FHFs in cardiomyocytes, starting with a proteomic approach to identify novel interacting proteins.
  
  
  RESULTS
  Affinity purification of FGF13 from rodent ventricular lysates followed by mass spectroscopy revealed an interaction with junctophilin-2, a protein that organizes the close apposition of the L-type Ca2+ channel CaV1.2 and the ryanodine receptor 2 in the dyad. Immunocytochemical analysis revealed that overall T-tubule structure and localization of ryanodine receptor 2 were unaffected by FGF13 knockdown in adult ventricular cardiomyocytes but localization of CaV1.2 was affected. FGF13 knockdown decreased CaV1.2 current density and reduced the amount of CaV1.2 at the surface as a result of aberrant localization of the channels. CaV1.2 current density and channel localization were rescued by expression of an shRNA-insensitive FGF13, indicating a specific role for FGF13. Consistent with these newly discovered effects on CaV1.2, we demonstrated that FGF13 also regulated Ca(2+)-induced Ca2+ release, indicated by a smaller Ca2+ transient after FGF13 knockdown. Furthermore, FGF13 knockdown caused a profound decrease in the cardiac action potential half-width.
  
  
  CONCLUSIONS
  This study demonstrates that FHFs not only are potent modulators of voltage-gated Na+ channels but also affect Ca2+ channels and their function. We predict that FHF loss-of-function mutations would adversely affect currents through both Na+ and Ca2+ channels, suggesting that FHFs may be arrhythmogenic loci, leading to arrhythmias through a novel, dual-ion channel mechanism.
authors.affiliation: Department of Medicine/Cardiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hennessey
authors.forename: Eric Q
authors.initials: EQ
authors.lastname: Wei
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D015222:Sodium Channels; C412507:junctophilin; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors; D002118:Calcium
keywords: arrhythmias, cardiac; cardiac electrophysiology; fibroblast growth factors; heart; ion channels/membrane transport; junctophilin